Speedy A governs non-homologous XY chromosome desynapsis as a unique prerequisite for XY loop-axis organization
In mouse early pachytene spermatocytes, the X and Y chromosomes undergo rapid non-homologous (NH) synapsis and desynapsis, but the functional significance remains unknown. Here, we report that pachynema-specific knockout of Speedy A (SpdyA) from telomeres caused persistent Y-X NH synapsis, with the entire Y axis synapsed onto the X axis. This persistent Y-X NH synapsis did not interrupt meiotic sex chromosome inactivation, recombination, or sex body formation, but it disrupted X-Y loop-axis organization and homologous X-Y desynapsis, leading to spermatocyte death. Similarly, persistent Y-X NH synapsis was also observed in pachytene spermatocytes lacking TRF1, where SpdyA was frequently lost from the X-Y non-pseudoautosomal region (non-PAR) telomeres. Mechanistic studies revealed that Serine 48 of SUN1 is a key SpdyA/CDK2 phosphorylation site required for Y-X NH desynapsis. We propose that SpdyA governs Y-X NH desynapsis by stabilizing the linkage between the X-Y non-PAR telomeres and their LINC complexes, and that this process is regulated independently from other aspects of pachynema progression. Our findings suggest a key role for Y-X NH desynapsis in establishing proper X-Y loop-axis organization.
Authors
- Louise T. Chow (ORCID: https://orcid.org/0000-0001-7586-9569)
- H. Lu (ORCID: https://orcid.org/0000-0001-6332-2785)
- Karen K. L. Chan (ORCID: https://orcid.org/0000-0001-9947-4713)
- Dongteng Liu (ORCID: https://orcid.org/0000-0002-9335-6940)
- Zexiong Lin
- Shu Deng (ORCID: https://orcid.org/0000-0001-8353-6705)
- Hengbin Wang (ORCID: https://orcid.org/0000-0003-2414-0609)
- Philipp Kaldis
- Chencheng Yao (ORCID: https://orcid.org/0000-0002-8820-7895)
- Zhe Hu (ORCID: https://orcid.org/0000-0001-6764-5610)
- Yanyan Li (ORCID: https://orcid.org/0000-0002-8109-7574)
- Kui Liu (ORCID: https://orcid.org/0000-0002-7519-3332)
- Zheng Li (ORCID: https://orcid.org/0000-0002-0062-2198)
- Yu Zhao (ORCID: https://orcid.org/0000-0002-2844-993X)
- Binjie Jiang
- William S.B. Yeung (ORCID: https://orcid.org/0000-0003-0670-0879)
- Dongliang Li (ORCID: https://orcid.org/0009-0003-7328-784X)
- Xudong Zhao
Institutions
- Shanghai Jiao Tong University (CN)
- Virginia Commonwealth University (US)
- Lund University (SE)
- University of Alabama at Birmingham (US)
- Shanghai First People's Hospital (CN)
- University of Hong Kong - Shenzhen Hospital (CN)
- HKU-Pasteur Research Pole (HK)
- University of Hong Kong (HK)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2025-08-18
- DOI
- https://doi.org/10.1038/s44318-025-00528-8
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Sanming Project of Medicine in Shenzhen
- National Key Research and Development Program of China
- Science and Technology Planning Project of Shenzhen Municipality
- Shenzhen Science and Technology Innovation Program